The Itch Cycle
Allergic skin disease is one of the most common conditions treated by veterinarians. Itching and scratching are hallmark clinical signs in dogs. It can be caused by a cycle of events that promotes neuronal itch stimulation, inflammation and scratching. This cycle can be triggered when allergens cross the skin barrier and activate T cells.
Historically, allergic skin disease was thought of as a Type 1 hypersensitivity reaction, mediated by inhaled allergens, cutaneous mast cells and allergen-specific IgE. However, our understanding of immune-mediated responses is evolving. Research now suggests that an over activation and release of pruritogenic cytokines and pro-inflammatory cytokines are at the centre of this condition.
Allergic skin disease begins with sensitization a process in which the initial exposure to allergens triggers a biologic response in the dog. For example, house dust mites that can be found in bedding and elsewhere in the environment can produce allergens that are viewed as a common trigger of allergic skin disease. These allergens can travel into the skin of a dog by crossing the epidermis, which can sometimes have defects in its barrier function. Such allergens can then be engulfed by antigen presenting cells found within the epidermis.
Antigen presenting cells migrate from the epidermis into the dermis and into a regional lymph node, where they trigger the activation of naïve T cells. This results in the polarization of T cells, which then release cytokines such as Interleukin-4 (IL-4) and Interleukin-13 (IL-13). Such cytokines can activate B cells, which then release allergen-specific IgE antibodies. The activated T cells then migrate to the dermal layer of the skin from the lymphatic system where the cytokines they release orchestrate a continuous cycle of itch and inflammation.
In summary, allergens cross into the skin, where they are ingested by antigen presenting cells. These cells then travel into lymph nodes where they trigger the activation of T cells and the release of cytokines and allergen specific IgE.
Neuronal Itch Stimulation
Following sensitization, immune cells within the skin are primed to rapidly recognize the allergen when it is presented again. So that when an antigen-presenting cell is exposed to the same allergen it can rapidly trigger the activation of T cells, which in turn release pruritogenic cytokines such as Interleukin-31 (IL-31). Interleukin-31 (IL-31) then travels and binds to receptors found on the surface of neurons. This interaction triggers the activation of Janus Kinase enzymes, or JAKs, which can stimulate the transmission of a signal along the nerve to the brain that promotes itching. Neuronal stimulation within the skin is a key component in the cycle of itch and inflammation in allergic dogs.
In summary, the re-exposure of antigen presenting cells to allergens induces the activation of T cells, which release cytokines such as Interleukin-31 (IL-31). IL-31 can then travel and bind to receptors on neurons. This interaction triggers the activation of JAKs, which induces a signal to the brain that triggers the itch response and scratching.
Inflammation is another major factor in the development of allergic skin disease. This process starts when cytokines are released from the activated T-cells. In addition, allergens bind to and cross-link IgE antibodies on the surface of mast cells. This interaction causes mast cells to release more pro-inflammatory cytokines and other inflammatory mediators. Pro-inflammatory cytokines recruit additional cells such as neutrophils and eosinophils from the blood into the dermis and promote their survival and expansion through the activation of pathways such as JAK. Infiltration of cells in the dermis results in inflammation that manifests clinically as redness of the skin. As more cells enter the dermis it becomes thicker, accompanied by epidermal hyperplasia.
In summary, the activation of mast cells within the dermis induces the release of pro-inflammatory mediators and cytokines. Such factors promote the recruitment of other immune cells. The activation of JAKs on the surface of these immune cells mediates the survival and expansion of the cells. The infiltration of immune cells into the skin promotes inflammation and epidermal hyperplasia. This process perpetuates the cycle of itch and inflammation, and contributes to the accompanying chronic changes to the skin, and an on going worsening of the barrier function.
A key therapeutic challenge for clinicians is finding a way to stop the neuronal itch stimulation and inhibit all aspects of the cycle – halting the inflammatory process, without causing systemic side effects.
The most common treatment prescribed, corticosteroids, stops the inflammation and related itching but have non-target effects on multiple organ systems including the liver, adrenal glands, and kidneys, and when used in excessive amounts, can have serious medical consequences. To avoid this practitioners often rely on a multimodal approach.
Increased understanding of the biochemical pathways in the cell and how cytokine signalling is controlled at a molecular level can provide alternative drug targets in the development of new pharmaceutical and biological approaches. By targeting the inhibition of JAK, new therapies could decrease the activity of pruritogenic and pro-inflammatory cytokines – stopping the continuous cycle of itch and inflammation and thereby restoring the quality of life for the dogs and their owners.
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